Secreted Protein, Acidic, Rich in Cysteines (SPARC), also known as osteonectin, is a 281 amino acid glycoprotein which is expressed in the human body.
The expression of SPARC is developmentally regulated, with SPARC being predominantly expressed in tissues undergoing remodeling during normal development or in response to injury. See, e.g., Lane et al., FASEB J., 8, 163-173 (1994). For example, high levels of SPARC protein are expressed in developing bones and teeth, principally osteoblasts, odontoblasts, perichondrial fibroblasts, and differentiating chondrocytes in murine, bovine, and human embryos. SPARC also plays important roles in cell-matrix interactions during tissue remodeling, wound repair, morphogenesis, cellular differentiation, cell migration, and angiogenesis, including where these are associated with disease states. For example, SPARC is expressed in renal interstitial fibrosis, and plays a role in the host response to pulmonary insults, such as bleomycin-induce pulmonary fibrosis.
SPARC also is upregulated in several aggressive cancers, but is absent from the vast majority of normal tissues. See, e.g., Porter et al., J. Histochem. Cytochem., 43, 791 (1995) and other references identified below. Indeed, SPARC expression is induced among a variety of tumors (e.g., bladder, liver, ovary, kidney, gut and breast). For example, in bladder cancer, SPARC expression has been associated with advanced carcinoma, with invasive bladder tumors of stage T2 or greater being shown to express higher levels of SPARC relative to bladder tumors of stage T1 (or less superficial tumors). See, e.g., Yamanaka et al., J. Urology, 166, 2495-2499 (2001). In meningiomas, SPARC expression has been associated with invasive tumors only. See, e.g., Rempel et al., Clincal Cancer Res., 5, 237-241 (1999). SPARC expression also has been detected in 74.5% of in situ invasive breast carcinoma lesions (see, e.g., Bellahcene et al., Am. J. Pathol., 146, 95-100 (1995)), and 54.2% of infiltrating ductal carcinoma of the breast. See, e.g., Kim et al., J. Korean Med. Sci., 13, 652-657 (1998). SPARC expression also has been associated with frequent microcalcification in breast cancer. See, e.g., Bellahcene et al., supra (suggesting that SPARC expression may be responsible for the affinity of breast metastases for the bone).
While SPARC possesses a number of properties, one that has been exploited is its ability to bind albumin. See, e.g., Schnitzer, J. Biol. Chem., 269, 6072 (1994). One example of the use of this property is in a FDA-approved solvent-free formulation of paclitaxel indicated in the treatment of metastatic breast cancer, Abraxane® (Abraxis BioScience, Inc., Santa Monica, Calif.). Nab-Paclitaxel utilizes the natural properties of albumin to reversibly bind paclitaxel, transport it across the endothelial cell, and concentrate it in areas of tumor. More specifically, the mechanism of drug delivery involves, in part, glycoprotein 60-mediated endothelial cell transcytosis of paclitaxel-bound albumin and accumulation in the area of tumor by albumin binding to SPARC. Clinical studies have shown that nab-paclitaxel is significantly more effective than other paclitaxel formulations, almost doubling the response rate, increasing time to disease progression and increasing survival in second-line patients. See Gradishar, Expert Opin. Pharmacother. 7(8):1041-53 (2006).
SPARC has affinity for a wide variety of ligands other than albumin, including cations (e.g., Ca2+, Cu2+, Fe2+), growth factors (e.g., platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF)), extracellular matrix (ECM) proteins (e.g., collagen I-V and collagen IX, vitronectin, and thrombospondin-1), endothelial cells, platelets, and hydroxyapaptite. As disclosed herein, SPARC also interacts with Procaspase 8.
A cascade of protease reactions is responsible for the apoptotic changes observed in mammalian cells undergoing programmed cell death or apoptosis. This cascade involves members of the aspartate-specific cysteine proteases of the ICE/CED3 family, also known as the Caspase family. A variety of stimuli can trigger apoptosis and two major apoptotic signaling pathways, “extrinsic” and “intrinsic”, converge biochemically leading to its execution (FIG. 1A). The extrinsic pathway is triggered by the activation of death receptors, such as Fas; the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, DR4 or DR5; or tumor necrosis factor receptor, which trigger death signals when bound by their natural ligands. Ligand binding to the receptor recruits adaptor proteins, such as Fas-associated death domain (FADD), which recruits Procaspase 8 to form death inducing signaling complexes (DISCs).
caspase 8 is activated at DISCs (i.e., converted from Procaspase 8 to Caspase 8 by peptide cleavage), leading to downstream pro-apoptotic events. The intrinsic pathway is centered around the mitochondria which is key in regulating the balance between pro- and anti-apoptotic factors, such as anti-apoptotic members Bcl-2, Bcl-XL and pro-apoptotic members Bax, Bak and Bok. It can be triggered by a number of stimuli., including agents that cause DNA damage or growth factor deprivation. This leads to the permeabilization of the mitochondrial membrane, the release of cytochrome c into the cytosol, which then interacts with APAF-1 to recruit Caspase 9, resulting in cleavage of executioner Caspases and apoptosis. The convergence of the extrinsic and intrinsic pathways occur when Caspase 8 activates Bid, a Bcl-2 family member that can trigger downstream targets to initiate the intrinsic apoptotic pathway.